PPARαcontributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis

Acute kidney injury (AKI) dramatically increases sepsis mortality, but AKI diagnosis is delayed when based on serum creatinine (SCr) changes, due in part, to decreased creatinine production. During experimental sepsis, we compared serum cystatin C (sCysC), SCr, and blood urea nitrogen (BUN) to inulin glomerular filtration rate (iGFR) before or 3–18 h after cecal ligation and puncture (CLP)-induced sepsis in CD-1 mice. sCysC had a faster increase and reached peak levels more rapidly than SCr in both sepsis and bilateral nephrectomy (BiNx) models. sCysC was a better surrogate of iGFR than SCr during sepsis. Combining sCysC with SCr values into a composite biomarker improved correlation with iGFR better than any biomarker alone or any other combination. We determined the renal contribution to sCysC handling with BiNx. sCysC and SCr were lower post-BiNx/CLP than post-BiNx alone, despite increased inflammatory and nonrenal organ damage biomarkers. Sepsis decreased CysC production in nephrectomized mice without changing body weight or CysC space. Sepsis decreased sCysC production and increased nonrenal clearance, similar to effects of sepsis on SCr. sCysC, SCr, and BUN were measured 6 h postsepsis to link AKI with mortality. Mice with above-median sCysC, BUN, or SCr values 6 h postsepsis died earlier than mice with below-median values, corresponding to a substantial AKI association with sepsis mortality in this model. sCysC performs similarly to SCr in classifying mice at risk for early mortality. We conclude that sCysC detects AKI early and better reflects iGFR in CLP-induced sepsis. This study shows that renal biomarkers need to be evaluated in specific contexts.

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Furosemide reverses medullary tissue hypoxia in ovine septic acute kidney injury

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00371.2018 ◽

2019 ◽

Vol 317 (2) ◽

pp. R232-R239 ◽

Cited By ~ 4

Author(s):

Naoya Iguchi ◽

Yugeesh R. Lankadeva ◽

Trevor A. Mori ◽

Eduardo A. Osawa ◽

Salvatore L. Cutuli ◽

...

Keyword(s):

Acute Kidney Injury ◽

Oxygen Consumption ◽

Oxygen Delivery ◽

Rapid Development ◽

Kidney Injury ◽

Experimental Sepsis ◽

Thick Ascending Limb ◽

Medullary Tissue ◽

Fractional Excretion Of Sodium ◽

Renal Oxygen

In experimental sepsis, the rapid development of renal medullary hypoxia precedes the development of acute kidney injury (AKI) and may contribute to its pathogenesis. We investigated whether inhibiting active sodium transport and oxygen consumption in the medullary thick ascending limb with furosemide attenuates the medullary hypoxia in experimental septic AKI. Sheep were instrumented with flow probes on the pulmonary and renal arteries and fiber optic probes to measure renal cortical and medullary perfusion and oxygen tension (Po2). Sepsis and AKI were induced by infusion of live Escherichia coli. At 24 h of sepsis there were significant decreases in renal medullary tissue perfusion (1,332 ± 233 to 698 ± 159 blood perfusion units) and Po2 (44 ± 6 to 19 ± 6 mmHg) (both P < 0.05). By 5 min after intravenous administration of furosemide (20 mg), renal medullary Po2 increased to 43 ± 6 mmHg and remained at this normal level for 8 h. Furosemide caused transient increases in fractional excretion of sodium and creatinine clearance, but medullary perfusion, renal blood flow, and renal oxygen delivery were unchanged. Urinary F2-isoprostanes, an index of oxidative stress, were not significantly changed at 24 h of sepsis but tended to transiently decrease after furosemide treatment. In septic AKI, furosemide rapidly restored medullary Po2 to preseptic levels. This effect was not accompanied by changes in medullary perfusion or renal oxygen delivery but was accompanied by a transient increase in fractional sodium excretion, implying decreased oxygen consumption as a mechanism.

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NMR-Based Serum and Urine Metabolomic Profile Reveals Suppression of Mitochondrial Pathways in Experimental Sepsis-Associated Acute Kidney Injury

AJP Renal Physiology ◽

10.1152/ajprenal.00582.2020 ◽

2021 ◽

Author(s):

Stephen Wade Standage ◽

Shenyuan Xu ◽

Lauren Brown ◽

Qing Ma ◽

Adeleine Koterba ◽

...

Keyword(s):

Gene Expression ◽

Acute Kidney Injury ◽

Kidney Function ◽

Systemic Inflammation ◽

Kidney Tissue ◽

Kidney Injury ◽

Acid Oxidation ◽

Experimental Sepsis ◽

Metabolic Derangement ◽

Serum And Urine

Sepsis-associated acute kidney injury (SA-AKI) is a significant problem in the critically ill that causes increased death. Emerging understanding of this disease implicates metabolic dysfunction in its pathophysiology. This study sought to identify specific metabolic pathways amenable to potential therapeutic intervention. Using a murine model of sepsis, blood and tissue samples were collected for assessment of systemic inflammation, kidney function, and renal injury. Nuclear magnetic resonance (NMR)-based metabolomics quantified dozens of metabolites in serum and urine which were subsequently submitted to pathway analysis. Kidney tissue gene expression analysis confirmed implicated pathways. Septic mice had elevated circulating levels of inflammatory cytokines and increased levels of blood urea nitrogen and creatinine, indicating both systemic inflammation and poor kidney function. Renal tissue showed only mild histologic evidence of injury in sepsis. NMR metabolomic analysis identified the involvement of mitochondrial pathways associated with branched-chain amino acid (BCAA) metabolism, fatty acid oxidation, and de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis in SA-AKI. Renal cortical gene expression of enzymes associated with those pathways was predominantly suppressed. Similar to humans, septic mice demonstrate renal dysfunction without significant tissue disruption, pointing to metabolic derangement as an important contributor to SA-AKI pathophysiology. Metabolism of BCAAs and fatty acids and NAD+ synthesis, which all center on mitochondrial function, appear to be suppressed. Developing interventions to activate these pathways may provide new therapeutic opportunities for SA-AKI.

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How can antibiotics worsen acute kidney injury but improve survival in experimental sepsis?*

Critical Care Medicine ◽

10.1097/ccm.0b013e318236e162 ◽

2012 ◽

Vol 40 (2) ◽

pp. 685-686 ◽

Cited By ~ 2

Author(s):

Ana C. P. Souza ◽

Peter S. T. Yuen

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Experimental Sepsis

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Cell-free hemoglobin augments acute kidney injury during experimental sepsis

AJP Renal Physiology ◽

10.1152/ajprenal.00375.2018 ◽

2019 ◽

Vol 317 (4) ◽

pp. F922-F929 ◽

Cited By ~ 5

Author(s):

Ciara M. Shaver ◽

Melinda G. Paul ◽

Nathan D. Putz ◽

Stuart R. Landstreet ◽

Jamie L. Kuck ◽

...

Keyword(s):

Acute Kidney Injury ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Filtration Rate ◽

Molecular Mechanisms ◽

Kidney Injury ◽

Experimental Sepsis ◽

Tubular Injury ◽

Free Hemoglobin ◽

Human Sepsis

Acute kidney injury is a common complication of severe sepsis and contributes to high mortality. The molecular mechanisms of acute kidney injury during sepsis are not fully understood. Because hemoproteins, including myoglobin and hemoglobin, are known to mediate kidney injury during rhabdomyolysis, we hypothesized that cell-free hemoglobin (CFH) would exacerbate acute kidney injury during sepsis. Sepsis was induced in mice by intraperitoneal injection of cecal slurry (CS). To mimic elevated levels of CFH observed during human sepsis, mice also received a retroorbital injection of CFH or dextrose control. Four groups of mice were analyzed: sham treated (sham), CFH alone, CS alone, and CS + CFH. The addition of CFH to CS reduced 48-h survival compared with CS alone (67% vs. 97%, P = 0.001) and increased the severity of illness. After 24 and 48 h, CS + CFH mice had a reduced glomerular filtration rate from baseline, whereas sham, CFH, and CS mice maintained baseline glomerular filtration rate. Biomarkers of acute kidney injury, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), were markedly elevated in CS+CFH compared with CS (8-fold for NGAL and 2.4-fold for KIM-1, P < 0.002 for each) after 48 h. Histological examination showed a trend toward increased tubular injury in CS + CFH-exposed kidneys compared with CS-exposed kidneys. However, there were similar levels of renal oxidative injury and apoptosis in the CS + CFH group compared with the CS group. Kidney levels of multiple proinflammatory cytokines were similar between CS and CS + CFH groups. Human renal tubule cells (HK-2) exposed to CFH demonstrated increased cytotoxicity. Together, these results show that CFH exacerbates acute kidney injury in a mouse model of experimental sepsis, potentially through increased renal tubular injury.

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